Lymphatic network drainage resolves cerebral oedema and facilitates recovery from experimental cerebral malaria

Whilst brain swelling, associated with fluid accumulation, is a known feature of paediatric cerebral malaria (CM), how fluid and macromolecules are drained from the brain during recovery from CM is unknown. Using the experimental cerebral malaria model (ECM), we show that fluid accumulation in the brain during CM is driven by vasogenic oedema, and not by perivascular cerebrospinal fluid (CSF) influx. Fluid and molecules were removed from the brain extremely quickly in mice with ECM to the deep cervical lymph nodes (dcLNs), predominantly through basal routes and across the cribriform plate and the nasal lymphatics. In agreement, ligation of the afferent lymphatic vessels draining to the dcLNs significantly impaired fluid drainage from the brain, sustained brain swelling, and lowered anti-malarial drug recovery from the ECM syndrome. Collectively, our results show that CM is not due to damaged CNS fluid drainage pathways and provide new insight into the pathways that coordinate recovery from CM.